The mitochondrial aldehyde dehydrogenase (ALDH2) is the major ALDH isozyme involved in acetaldehyde metabolism. It is well established that a single nucleotide substitution (G to A) which results in the amino acid change (Glu487Lys) leads to dominant inactivation of ALDH2 activity. Our data indicated that the recombinant human ALDH2 variant protein interacted with the mouse ALDH2 protein and dominantly inhibited the activity of the mouse enzyme. The genetic polymorphism is the cause of the flushing response observed in many Asian people following alcohol intake. Although the ALDH2-2 allele has been shown to have a protective role against alcoholism, the physiological role of this enzyme is still unclear. To further examine the physiological role of ALDH2 in alcohol-mediated tissue damage, drinking behavior and metabolism of endogenous and exogenous substrates, we produced transgenic mice carrying the human ALDH2 variant (Haldh2-2). Currently, we have established two independent lines of Haldh2 transgenic mice. Human ALDH2 protein was expressed in all tissues examined and expression of human ALDH2-2 inhibited mouse ALDH2 enzyme activity in transgenic mice. We also observed that the FVB/N background strain mice showed fear, avoidance and escape behavior 3 days after treatment with 20% ethanol but these changes in behavior were not evident in the transgenic mice exposed to ethanol (p<0.001). To correlate the apparent behavioral change with levels of neurotransmitters and to study the role of ALDH2 in endobiotic metabolism, the levels of various monoamine neurotransmitters are being determined by HPLC. Our data also indicate that both male and female transgenic mice showed 40-50% higher acetaldehyde levels in the livers than the FVB/N background mice (n=6 for each group, p<0.01). We are determining the drinking preference in a two-bottle choice paradigm. Our data collected so far indicate that transgenic mice carrying the Haldh2-2 can be a valuable model to study the role of ALDH in behavior, neurotransmitter metabolism and drinking preference. In order to have clear results for the physiological roles of ALDH2, we have also prepared a DNA vector to prepare knock-out mice deficient of mouse ALDH2 gene by gene disruption method.